Ointments containing oil-soluble antioxidants



Patented Jan. 15, 1952 OINTMENTS CONTAINING OIL- SOLUBLE AN TIOXIDAN TS George W. Rigby, Wilmington, Del., assignor, by memo assignments, to the United States of America as represented by the Secretary of War No Drawing. Application March 6, 1945, Serial No. 581,323

17 Claims.

This invention relates to therapeutic compositions and more particularly it relates to ointments for arsenic therapy.

A number of common ointment bases such as, for example, those containing peanut oil, lanolin and the like as the vehicle for the medicament are suitable in consistency and spreading quality for the preparation of ointments containing 2,3-dimercaptopropanol as the therapeutic agent. However, these 2,3-dimercaptopropanol ointments are susceptible to oxidation when exposed to air. Oxygen readily reacts with the thiol groups of the dimercaptopropanol to form polymeric disulfides which are therapeutically inactive. Such ointments thus lose their efiicacy on intermittent or continuous exposure to air. The particular sensitivity of the dimercaptopropanol and the necessity for keeping these compositions at a precise level of therapeutic activity creates a special problem, to which the application of the general antioxidant art does not provide a solution.

'An object of this invention is to provide more useful therapeutic compositions containing 2,3- dimercaptopropanol than have heretofore been available. A further object is to provide ointments containing 2,3-dimercaptopropanol which retain their efiicacy for long periods, particularly when they are exposed to air. More specifically it is an object of this invention to retard the rate of oxidation of 2,3-dimercaptopropanol in ointments containing this therapeutic agent.

These objects are accomplished by admixing with an oily vehicle the desired medicament, viz., 2,3-dimercaptopropanol, and a small amount of an oil soluble anti-oxidant, whereby there is obtained an ointment comprising these components which is useful in arsenic therapy and more stable than ointments previously available.

In the practice of the invention, pure 2,3-dimercaptopropanol, obtainable by the reaction of sodium hydrosulfide with glycerol dichlorohydrin, and about 0.5 to 2.0% of its weight of the oil-soluble anti-oxidant, are compounded at room temperature with a cold uniformly melt-blended oily base preferably comprising a fatty material such as peanut oil or lanolin or both. The oilscluble anti-oxidants which have given the best results are the tocopherols, preferably the mixture of the several isomers available as a fish oil distillate. The resulting ointments absorb oxygen at a considerably less rapid rate than similar ointments not containing an oil-soluble antioxidant.

The following examples illustrate the invention in greater detail.

In these examples proportions of ingredients are expressed as parts by weight unless otherwise specified.

Mixed natural tocopherols (4.0%) 0.05 2,3-dimercaptopropanol 5.00

All the above ingredients with the exception of the last two mentioned are heated together until a uniform melt is obtained. This melt is cooled with stirring to room temperature, and the tocopherols and 2,3-dimercaptopropanol then Worked into it with a spatula, putty knife, or an appropriate mechanical mixer designed for handling pasty masses. A composition useful for external arsenic therapy is obtained. Its 10W oxidation susceptibility is shown by the following test. An accurately weighed sample of the ointment is stored under pure oxygen at 50 C. and atmospheric pressure, and the amount of oxygen absorbed is measured after 48 hours. One part of the ointment absorbs only 4.6 10 part of oxygen under these conditions while an equal weight of an ointment containing the same ingredients in the same proportions, with the exception that no tocopherols are present, absorbs 10 10- part of oxygen.

Example II Parts Lanolin, anhydrous 80.0 Benzyl benzoate 10.0 Mixed natural tocopherols (40%) 0.1 2,3-dimercaptopropanol I- 10.0

The above ingredients are made up into an ointment in the manner given in Example I. One part of this ointment when tested as described in Example I, absorbs 2.7 l0- part of oxygen on exposure to pure oxygen for 48 hours at 50 C. A control ointment containing no added tocopherols absorbs 15.7 10- part of oxygen.

The examples illustrate the use of mixed tocopherols as the anti-oxidant for 2,3-dimercaptopropanol ointments. Instead of the mixed tocopherols, the individual alpha-, beta-, and gamma-tocopherols and other oil-soluble antloxidants, e. g., palmitoyl ascorbate and hydroquinone, which are not reactive with thiol groups,

may be used. The tocopherols are the most effective of these oil-soluble anti-oxidants. As previously indicated, they are commercially available as a 40% concentrate distilled from fish oil. More specifically, this concentrate is a distilled mixture of the alpha-, beta-, and gamma-tocopherols, and it may be used in the ointments of this invention without separation of the isomers or further purification. The individual tocopherols may be used, if desired, but they have different degrees of effectiveness. The alpha-tocopherol, for example, is somewhat less effective than the other isomers or the commercial mixture. The gamma-tocopherol is the most effective of the individual isomers.

The proportions of oil-soluble anti-oxidant employed in these ointments may vary over a wide range depending on the amount of 2, 3- dimercaptopropanol present and on the degree of oxygen exposure expected to be encountered. Thus, amounts ranging from 0.5% to 10.0% of the weight of the dimercaptopropanol may be used. Under mild conditions of exposure, 0.5% is sufficient, While 10.0% is required when the ointment is to be exposed to oxygen or air for long periods at relatively high temperatures. For ordinary exposures the preferred amount is 0.5% to 2.0% or" the weight of the dimercaptopropanol.

2, B-dimereaptopropanol is subject to other types of chemical transformation, such to polymeric sulfides by heat in the absence of oxygen, in contrast to disulfides formed by oxidation. In the present ointments, this type of transiormation may be minimized by careful control of water content, iron content, and pH. More specifically, the ointments of highest heat stability must (1) contain less than about 0.5% water, (2) contain less than 1 part per million, and preferably less than 0.5 part per million, of iron and other heavy metals, and (3) have a pH within the range of 4-5, an equilibrium value obtained with a pH meter and glass electrode on a portion of the aqueous layer obtained by treating a sample of the ointment with sufficient freshly boiled distilled Water to have a ratio or" Water to dimercaptopropanol of 99 to 1. These factors are controlled by (1) use of only anhydrous ingredients, (2) use of ingredients together containing less than the above-specified quantity of heavy metals, and formulating the ointments in vessels WhiCh'dO not introduce any more of these metals, and (3) the use of ingredients having a neutral or slightly acid reaction or by adding suflicient acid to the f nal ointment to bring its pH Within the preferred range.

In place of the specific oily vehicles disclosed in the examples, other oily bases may be used in these ointments. For example, other nondrying vegetable oils such as olive oil and castor oil, non-drying animal oils, or other types of non-drying oils such as mineral oils may be used if desired.

The ointments of this invention are of great value in neutralizing chemical warfare vesicants containin arsenic, particularly the arsines, and in arsenic and cadmium therapy in general. The presence of the oil-soluble anti-oxidant renders them sufficiently inert to oxidation to permit their use under practical conditions Without excessive loss in efficacy.

Having thus described my invention, what I claim as new and wish to secure by Lette s Patent is:

l. A stable ointment comprising an oily vehicle, 2,3-dimercaptopropanol, and an oil-soluble antioxidant for the mercapto compound selected from the group consisting of tocopherol and palmitoyl ascorbate, the anti-oxidant being present in an amount of at least 0.5 per cent by weight of the said mercapto compound.

2. An anti-vesicant composition containing, 2,3-dimercaptopropanol, and an anti-oxidant for said mercapto compound comprising tocopherol in an amount of at least 0.5 per cent by weight of the said mercapto compound.

3. An anti-vesicant composition containing, 2, 3-dimercaptopropanol, and an anti-oxidant for said mercapto compound comprising tocopherol in an amount of from 0.5-10% of the weight of said mercapto compound.

4. A stable ointment for arsenic and cadmium therapy containing, non-drying oils, 2, 3-dimercaptopropanol, and an anti-oxidant for said mercapto compound comprising tocopherol in an amount of at least 0.5 per cent by weight .of the said mercapto compound.

5. A stable ointment for arsenic and cadmium therapy containing, non-drying oils, 2, 3-dimercaptopropanol, and an anti-oxidant for said mercapto compound comprising tocopherol in an amount of from 0.5-10% of the Weight of said mercapto compound.

6. A stable ointment for arsenic and cadmium therapy containing, non-drying oils, 2, 3-dimercaptopropanol, and an anti-oxidant for said mercapto compound comprising mixed natural tocopherols in an amount of at least 0.5 per cent by weight of the said mercapto compound.

2'. A stable ointment for arsenic and cadmium therapy containing, non-drying oils, 2, 3-dimercaptopropanol, and an anti-oxidant for said mercapto compound comprising mixed natural tocopherols in an amount of from 0.5-,l0% of the weight of said mercapto compound.

8. A stable ointment for arsenic and cadmium therapy containing, non-drying oils, 2, 3-dimercaptopropanol, and an anti-oxidant for said mercapto compound comprising mixed natural tocopherols in an amount of from 0.52.0% of the weight of said mercapto compound.

9. A stable ointment for arsenic and cadmium therapy containing, non-drying oils, 2, 3-dimercaptopropanol, and anti-oxidant for said mercapto compound consisting of gamma-tocopherol in an amount of at least 0.5 per cent by weight of the said mercapto compound.

10. A stable ointment for arsenic and cadmium therapy containing, non-dryin vegetable oils, 2, B-dimercaptopropanol, and an anti-oxidant for said mercapto compound comprising mixed natural tocopherols in an amount of from 0.5- 10% of the weight of said mercapto compound.

11. A stable ointment as set forth in claim 9 characterized in that it-has a pH range of from 4-5 and contains less than about 0.5% water and less than 1 part per million of heavy metals.

12. A stable ointment for arsenic and cadmium therapy containing, non-drying animal oils,

, 2, 3-dimercaptopropanol, and an anti-oxidant for said mercapto compound comprising mixed natural tocopherols in an amount of from 0.5- 10% of the weight of said mercapto compound.

13. A stable ointment as set forth in claim 11 characterised in that it has a pH range of from 45 and contains less than about 05% water and less than 1 part per million of heavy metals. 14. A stable ointment for arsenic and cadmium therapy containing, peanut oil, 2, 3-dimercaptopropanol, and an anti-oxdiant for said mercapto compound comprising mixed natural tocopherols in an amount of from 05-10% of the weight of said mercapto compound.

15. A stable ointment for arsenic and cadmium therapy containing, anhydrous lanolin, 2, 3-dimercaptopropanol, and an anti-oxidant for said mercapto compound comprising mixed natural tocopherols in an amount of from 05-10% of the weight of said mercapto compound.

16. A stable ointment for arsenic and cadmium therapy comprising in parts by weight:

Peanut 011 36.95 Lanolin, anhydrous 8.00 Cetyl alcohol 10.00 Glyceryl monostearate 10.00 White petrolatum, soft 25.00 Benzyl benzoate 5.00 Mixed natural tocopherols 0.05 2, 3-dimercaptopropanol 5.00

6 17. A stable ointment for arsenic and cadmium therapy comprising in parts by Weight:

Lanolin, anhydrous 80.0 Benzyl benzoate 10.0 Mixed natural tocopherols, 0.1 2, 3-dimercaptopropanol 10.0

GEORGE W. RIGBY.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS 

1. A STABLE OINTMENT COMPRISING AN OILY VEHICLE, 2,3-DIMERCAPTOPROPANOL, AND AN OIL-SOLUBLE ANTIOXIDANT FOR THE MERCAPTO COMPOUND SELECTED FROM THE GROUP CONSISTING OF TOCOPHEROL AND PALMITOYL ASCORBATE, THE ANT-OXIDANT BEING PRESENT IN AN AMOUNT OF AT LEAST 0.5 PER CENT BY WEIGHT OF THE SAID MERCAPTO COMPOUND.
 2. AN ANTI-VESICANT COMPOSITION CONTAINING, 2,3-DIMERCAPTOPROPANOL, AND AN ANTI-OXIDANT FOR SAID MERCAPTO COMPOUND COMPRISING TOCOPHEROL IN AN AMOUNT OF AT LEAST 0.5 PER CENT BY WEIGHT OF THE SAID MERCAPTO COMPOUND. 